The primary goals of this program are understanding (a) the structure and function of neurotransmitter systems in the overall operation of the mammalian central nervous system (CNS), and (b) the molecular mechanism of action of drugs which act on the CNS. Also under study are the mechanism(s) through which the immune and other peripheral systems are influenced by the CNS in normal and disease states. It is now clear that many of these systems function by interaction of cell receptors with endogenous ligands, and that production of the pharmacological effects of diverse classes of drugs requires drug-receptor interaction as a first step. Many unique opportunities for dramatic advances in the understanding of these systems have been presented by these observations but exploitation of such opportunities requires highly selective drugs as probes of the systems. The multidisciplinary approach utilized in this program employs rational drug design based on structure-activity relations and molecular modeling, modern organic chemical synthesis, pharmacology, biochemistry, immunology and requires collaboration with other appropriate disciplines. Elucidation of the molecular structure and mechanism of action of the ligand-receptor systems and the molecular mechanism of action of drugs and their antagonists will provide new opportunities for the design of superior drugs for many clinical situations and new insight into disorders which are now little understood. Areas now under active investigation include (a) central opioid receptor subtypes, (b) opioid receptors on components of the immune system, (c) mechanisms of narcotic tolerance and dependence (d) peripheral benzodiazepine receptors (e) the benzodiazepine receptor-coupled gamma aminobutyric acid gated chloride ionophore. Synthetic programs are continuing to develop new ligands for imaging brain drug receptors by positron emission tomography (PET) and single photon emission computed tomography (SPECT) scanning. The recently developed NIH Opiate Total Synthesis continues to be employed to provide previously inaccessible unnatural enantiomers of opiates and derivatives as new pharmacological agents and research tools. The recent observation that opiate receptors in the periaqueductal grey matter of rat brain mediate morphine induced immunosuppression has provided impetus for a much more detailed, ongoing study of the effects of opioids on immune function.